Chronic hepatitis B (CHB) is a major public health problem affecting up to 400 million people globally. Complications of CHB including liver failure and hepatocellular carcinoma (HCC) result in 1.2 million deaths per year, making CHB the 10th leading cause of mortality worldwide. The natural history of CHB is complex and variable. Many viral and host factors have been implicated in disease progression and hepatocarcinogenesis but most of these conclusions have been based on retrospective analyses with limited longitudinal data. Currently, six agents are FDA-approved for the treatment of CHB. Each of these agents, given as monotherapy, has been shown to produce virological, biochemical and histological benefits for both HBeAg positive and negative CHB. However, each are associated with limitations. The significant side-effect profile of interferon, for example, limits its long-term use. The approved oral agents are tolerable even with prolonged use but drug resistance has been identified with each of them. To date, the limited data on combination therapy with nucleoside analogue and pegylated interferon (PEGIFN) or two nucleos(t)ide analogues given for one year does not show their superiority in durability of response compared to monotherapy. However, there have been no studies to address the efficacy of prolonged combination therapy. In this proposal, by working collaboratively with the 10 clinical centers, the Data Coordinating Center (DCC), Virology Center, and Immunology Center within the NIH HBV network, we plan to (1)construct a prospective, comprehensive patient database that includes demographic and clinical features, viral factors, liver histology and radiological findings that will enable us to examine the natural history of hepatitis B and to identify predictors of disease progression and recovery using both cross-sectional and longitudinal clinical data;and (2) design a 3-year, phase III, prospective, multicenter, randomized, open-label study to compare the efficacy and safety of entecavir (ETV) versus ETV and tenofovir (TDF) versus ETV and PEGIFN-alpha-2a for treatment naive patients with HBeAg positive and negative CHB. Patients randomized to the third arm will receive a 2-year course of PEGIFN and a 3-year course of ETV. ETV and TDF are structurally distinct, potent antiviral agents that do not have cross-resistance. We hypothesize that(1) both combination therapy arms will have higher rates of HBV DNA suppression and lower rates of resistance compared to ETV monotherapy;and (2) the combination of PEGIFN with ETV will produce the highest rates of both HBeAg and HBsAg seroconversion and, hence, durability of response. Collectively, the database and trial will yield rich data regarding natural history and optimal therapy for CHB.